The application proposes a four-year mentored research and training experience crafted to advance the candidate?s career as a leader in genomic medicine. The candidate earned a combined MD/PhD in Molecular and Human Genetics and is board certified in Pediatrics. His long-term career goal is to become an independently funded physician-scientist at a major academic center and to advance research efforts that integrate translational genomics with innovative strategies to determine pathogenicity of missense variants currently categorized as variants of uncertain significance (VUS). The proposed work leverages skills he developed during prior training and research and will form the basis for a successful R01 proposal. The career development plan includes milestone-based training in biomedical informatics (including the conferring of a Master?s degree), statistics, and the design and implementation of functional genomics experiments. The candidate will receive training in ethical and responsible conduct of research, communication skills, grant writing, and laboratory management via participation in core curricula, workshops, seminars, laboratory meetings, and local, national, and international presentations. The mentoring team for the proposed interdisciplinary project includes expertise in clinical, statistical, computational, and functional genomics. The primary mentor, Dr. Barak Cohen, is an experienced mentor and an expert in experimental and computational approaches for functional genomics evaluations. The co-mentors, Drs. Michael Province, Christina Gurnett, and David Ledbetter, each bring unique expertise and commitment to the candidate?s success. Additional members of the mentorship advisory committee include the long-term mentors of the candidate, Drs. F. S. Cole and John Constantino, and the neurofibromatosis expert, Dr. David Gutmann. Washington University School of Medicine (WUSM) provides an exceptional research and training environment, including resources from the McDonnell Genome Institute and the Institute for Informatics. The candidate has the full support of the Department of Pediatrics, which has a long history of training physician-scientists. The research proposed addresses a central problem in human genetics today, namely variant interpretation. This work will integrate 1) deep mutational scanning and experimental validation to determine pathogenicity of missense variants currently categorized as variants of uncertain significance (VUS), and 2) exome sequencing and linked Electronic Health Record data from >90,000 individuals for clinical validation. The well-studied NF1 tumor suppressor gene will serve as a model for developing best practices for variant interpretation. The work will directly impact the assessment and care of patients with NF1-related diseases and will serve as a template for generating similar models for a range of diseases. The candidate, his mentors, the Department, and WUSM are committed to his becoming an independent physician-scientist and leader in genomic medicine.